Water-soluble pharmaceutical compositions of hops resins

ABSTRACT

The present invention is drawn to water-soluble compositions for providing hops constituents, particularly alpha acids, iso-alpha acids, and beta acids. A pharmaceutical gel composition can comprise a hops extract and a surfactant. Such compositions can be formulated into products for various therapeutic applications, including oral and topical uses. Such compositions can also be dissolved in water to yield a clear solution containing more dilute hops acids. The invention also provides methods of treatment comprising administering water-soluble hops compositions. The present invention is also drawn to methods for making water-soluble preparations of hops constituents.

The present application is a continuation of U.S. patent applicationSer. No. 13/311,288, filed on Dec. 5, 2011, which is a continuation ofU.S. patent application Ser. No. 11/409,521, filed on Apr. 21, 2006,both of which are incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to unique pharmaceutical compositions comprisingwater soluble extracts of hops resins, and methods for preparation ofsuch compositions. The invention also relates to methods for treatingconditions in a subject using water-soluble hops compositions.

BACKGROUND OF THE INVENTION

Many botanical substances contain chemicals that have been found to beuseful for the therapeutic treatment of various medical conditions.Since these chemicals are often present in very small amounts,techniques have been developed to extract these substances and toconcentrate the therapeutically active agents. Various methods areavailable for extraction and purification of such substances, includingthe use of organic solvents, microwave systems, and supercritical CO₂extraction. Organic solvent-based extractions utilize added solventsthat are evaporated to form a concentrated extract, which results in adamp, pasty mass that is typically further spray-dried onto a carrierfor delivery. Alternatively, supercritical CO₂ extraction is anothermethod of collecting such extracts. This extraction method yields athick, high viscosity resin, oil, or other fluid-like material that canhave a honey-like consistency.

One pharmaceutically useful botanical substance is the extract of hops(Humulus lupulus L.). Hops cone flowers contain a variety of activeagents, including alpha acids, iso-alpha acids, and beta acids, as wellas a number of flavonoids and essential oils. Humulone, one of the alphaacids found in hops, has been demonstrated to suppress cyclooxygenase-2activity, inhibit angiogenesis, and decrease bone loss. Some otherbiologically relevant properties of hops constituents includeanti-inflammatory, antibacterial, antiviral, antifungal, estrogenic,anti-oxidant, anti-allergenic, anti-carcinogenic, and anti-proliferativeproperties.

As with other botanical substances, dried hops flowers contain verysmall amounts of alpha acids. Supercritical CO₂ extraction and othersolvent-based extractions of dried hops cones produce a thick,high-viscosity resin that can contain a high percentage of active hopsconstituents. While extraction is an effective means of providing alphaand beta acids in a highly concentrated form, the resulting extractshave very low solubility in water. This property can make digesting suchextracts difficult, resulting in delayed absorption of the acids anddelayed onset of certain therapeutic effects. It would therefore beuseful to provide the primary constituents of hops extracts informulations that are soluble in water. In addition, methods of makingsuch formulations from hops extract resin would be desirable.

SUMMARY OF THE INVENTION

It has been recognized that it would be advantageous to be able toformulate hops extract into water-soluble forms that can be used in oralor topical formulations. In accordance with this, a pharmaceutical gelcomposition can comprise from 0.2 wt % to 70 wt % hops extract, and from30 wt % to 99.8 wt % non-ionic surfactant. The gel composition can befree of visible particulates and be water-soluble. A clearpharmaceutical solution can be prepared therefrom by dissolving in waterto yield the clear solution. The clear solution can comprise from 0.0005wt % to 24.5 wt % alpha acids and from 0.0001 wt % to 12.5 wt % betaacids.

In these embodiments, the gel composition or the clear pharmaceuticalsolution can be formulated into various product forms such astoothpastes, creams, ointments, lotions, salves, nasal mists, and oralrinses.

In another embodiment, a method of making a water-soluble pharmaceuticalgel composition of hops extract can comprise the steps of heating awater-soluble non-ionic surfactant in a container to a temperature ofabout 90° F. to 250° F., while mixing the surfactant until it is clear;heating a hops extract to a temperature of about 90° F. to 120° F. (ahigher temperature, e.g., up to 250° F., may be desirable if the goal isisomerization of the alpha acids); and mixing an amount of the hopsextract with the surfactant so as to constitute from 0.2 wt % to 70 wt %hops extract and from 30 wt % to 99.8 wt % surfactant. The hops extractcan be sufficiently dispersed or dissolved in the surfactant so that thegel composition contains no visible particles of hops extract.

In another embodiment, a method of making a clear pharmaceuticalsolution can comprise dissolving or finely dispersing the gelcomposition described above, such as in water or an aqueous solventsystem, such that the clear pharmaceutical solution comprises from0.0005 wt % to 24.5 wt % alpha acids and from 0.0001 wt % to 12.5 wt %beta acids.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT(S)

Before particular embodiments of the present invention are disclosed anddescribed, it is to be understood that this invention is not limited tothe particular process and materials disclosed herein, as such can varyto some degree. It is also to be understood that the terminology usedherein is used for the purpose of describing particular embodiments onlyand is not intended to be limiting, as the scope of the presentinvention will be defined only by the appended claims and equivalentsthereof.

It is to be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the context clearly dictates otherwise.

As used herein, “administration,” and “administering” refer to themanner in which a drug, formulation, or composition is introduced ontoor into the body of a subject. Administration can be accomplished byvarious art-known routes such as topical, oral, parenteral, transdermal,inhalation, etc. Thus, topical administration can be achieved byapplying to intact or damaged skin, or to a tooth, gums, tongue, orother oral surface of a subject. An oral administration can be achievedby swallowing, chewing, or sucking an oral dosage form comprising activeagent(s). Parenteral administration can be achieved by injecting acomposition intravenously, intra-arterially, intramuscularly,intrathecally, or subcutaneously, etc. Transdermal administration can beaccomplished by applying, pasting, rolling, attaching, pouring,pressing, rubbing, etc., of a transdermal preparation onto a skinsurface. In some cases, it can be desirable to administer a compositionfor the purpose of having a therapeutic or hygienic effect in the oralcavity itself. In these cases, administration can be achieved by placingan amount of the composition into the mouth and spreading thecomposition on the desired oral surfaces either by moving the tongue, orby using an appropriate instrument such as a brush or a swab. These andadditional methods of administration are well known in the art.

The terms “effective amount,” and “sufficient amount” can be usedinterchangeably and refer to an amount of an ingredient which, whenincluded in a composition, is sufficient to achieve an intendedcompositional or physiological effect. Thus, a “therapeuticallyeffective amount” refers to a non-toxic, but sufficient amount of anactive agent, to achieve therapeutic results in treating a condition forwhich the active agent is known to be effective. Various biologicalfactors can affect the ability of a substance to perform its intendedtask. Therefore, a “sufficient amount” or a “therapeutically effectiveamount” can be dependent on such biological factors. Further, while theachievement of therapeutic effects can be measured by a physician orother qualified medical personnel using evaluations known in the art, itis recognized that individual variation and response to treatments canmake the achievement of therapeutic effects a subjective decision. Insome instances, a “sufficient amount” of an active agent can achieve atherapeutic effect that is measurable by the subject receiving theactive agent. The determination of an effective amount is well withinthe ordinary skill in the art of pharmaceutical, medicinal, and healthsciences.

The terms “supercritical carbon dioxide” and “supercritical CO₂” eachrefers to carbon dioxide gas that has been heated and pressurized untilit is beyond its critical state, e.g., above 310° C. and 73 atmospheres.Gases in this state have been found to be excellent solvents, possessinga pressure-tunable dissolving power, liquid-like density, and gas-liketransport properties. The term “supercritical carbon dioxide extraction”refers to a separation process using supercritical CO₂ as a solvent. Itshould be noted that there are various other steps that can be carriedout to modify the percentages of various constituents of an extractprepared using supercritical carbon dioxide extraction (as well as otherextraction methods), such as fractionation, TLC (thin layerchromatography), etc.,

The term “alpha acid(s)” refers to humulone, cohumulone, adhumulone,dihydrohumulone, dihydrocohumulone, dihydroadhumulone, or any mixturethereof. This term does not refer to the various isomers of these threecompounds, however. Instead, the term “iso-alpha acid(s)” refers toiso-humulone, iso-cohumulone, iso-adhumulone, trans-iso-humulone,cis-iso-humulone, trans-iso-cohumulone, cis-iso-cohumulone,cis-iso-adhumulone, trans-iso-adhumulone, dihydro-iso-humulone, anddihydro-iso-adhumulone, or any mixture thereof.

The term “beta acid(s)” refers to lupulone, colupulone, adlupulone,prelupulone, postlupulone, or any mixture thereof.

The term “surfactant” refers to substances comprising typicallyamphipathic molecules that have the effect of decreasing surface tensionin certain fluids, for example reducing the tension at a lipid/waterinterface. As used herein, a “non-ionic surfactant” is a surfactant thattends to have no net charge in neutral solutions.

As used herein, “solution” can refer to a preparation in which a firstcomposition is intermixed with a second composition. For the purposes ofthe present invention, the degree of intermixing can be such that thefirst composition is present in the solution as particles that are toosmall to be visible by the naked eye. These particles can be individualions, atoms, or molecules, or assemblages of such units that are smallenough to disperse throughout the preparation into a substantiallyrandom spatial distribution. Thus, the term “solution” encompasses bothsolubilized liquid mixtures or finely dispersed liquid mixtures,provided the “solution” appears clear to the naked eye.

The term “clear,” as used herein in reference to the compositions of thepresent invention, shall be understood to describe the visual appearancethat such solutions possess, i.e. that, when viewed in a transparentcontainer with the naked eye, objects can be seen through the solution,but no particulate matter can be seen in the solution itself. Under thisdefinition, “clear” can describe colorless solutions as well as thosehaving color of a hue and intensity that does not prevent it from beingseen through, e.g., pale color.

As used herein, “subject” refers to an animal, such as a mammal, thatcan benefit from the administration of the compositions or formulationsof the present invention. Most often, the subject will be a human.

The term “about” when referring to a numerical value or range isintended to encompass the values resulting from experimental error thatcan occur when taking measurements.

As used herein, a plurality of items, structural elements, compositionalelements, and/or materials can be presented in a common list forconvenience. However, these lists should be construed as though eachmember of the list is individually identified as a separate and uniquemember. Thus, no individual member of such list should be construed as ade facto equivalent of any other member of the same list solely based ontheir presentation in a common group without indications to thecontrary.

Concentrations, amounts, and other numerical data can be presentedherein in a range format. It is to be understood that such a rangeformat is used merely for convenience and brevity and should beinterpreted flexibly to include not only the numerical values explicitlyrecited as the limits of the range, but also to include all theindividual numerical values or sub-ranges encompassed within that rangeas if each numerical value and sub-range is explicitly recited. Forexample, a weight range of about 1 wt % to about 20 wt % should beinterpreted to include not only the explicitly recited concentrationlimits of about 1 wt % to about 20 wt %, but also to include individualconcentrations such as 2 wt %, 3 wt %, 4 wt %, and sub-ranges such as 5wt % to 15 wt %, 10 wt % to 20 wt %, etc.

In accordance with these definitions and recognitions, the presentinvention is drawn to pharmaceutical gel compositions comprising 0.2 wt% to 70 wt % of a hops extract and 30 wt % to 99.8 wt % of a non-ionicsurfactant. Though any extract can be used, preferably, the extract canbe a resin extract, such as that produced using CO₂ extraction or othersolvent extraction methods. According to one embodiment, apharmaceutical gel composition can include from 0.25 wt % to 49.5 wt %of a combination of alpha acids and iso-alpha acids, and from 0.05 wt %to 25 wt % beta acids. The non-ionic surfactant can be a single mono-,di-, or triglyceride, mono- or di-fatty acid ester of polyethyleneglycol, sorbitan fatty acid ester, polyglycolyzed glyceride, triblockcopolymer, or a mixture thereof. According to a particular embodiment,the non-ionic surfactant can be polyoxyl castor oil.

According to another embodiment of the invention, a pharmaceuticalcomposition can comprise the pharmaceutical gel composition dissolved inwater or aqueous solvent system to yield a clear solution containingfrom 0.0005 wt % to 24.5 wt % alpha acids and from 0.0001 wt % to 12.5wt % beta acids. In more particular aspects of this embodiment, thecomposition can be formulated into a product further comprisingadditives such as flavoring agents and coloring agents.

This being stated, the present invention is directed to methods andcompositions for providing therapeutically active constituents of hops,as well methods of making such compositions. Pharmaceutically usefulbotanical compounds are often only present in low amounts in theirrespective plants. The cone flower of hops (Humulus lupulus L.) is noexception, and has been found to contain a number of agents withpossible therapeutic applications. For example, dried hops flowerscontain small amounts of alpha acids and beta acids. To collect a moreconcentrated form of the active ingredients in hops, these ingredientscan be extracted and purified by various techniques, including organicsolvent extraction, microwave extraction, or supercritical CO₂extraction. While the present invention can utilize hops extractcollected by any of these or other techniques suitable for extractingplant materials, extracts produced by supercritical CO₂ extraction arepreferred in some embodiments for use in accordance with this invention.This process involves passing supercritical carbon dioxide gas throughhops powder, thereby dissolving the constituents into the gas. The gasis then recovered and depressurized, causing the dissolved materials toprecipitate out. If desired, the recovered gas can be re-pressurized andrecycled back through the hops for further extraction.

One advantage of supercritical CO₂ extraction over solvent-basedtechniques is that substantially no solvent residues remain with theextract. The resulting product is a thick, high-viscosity resin, oil, orother fluid-like material, which can be engineered to produce a veryhigh percentage of alpha acids, a much lower percentage of beta acids,and essentially no essential oils. Processes such as fractionation witha mineral salt or oxide/hydroxide, e.g., magnesium oxide, TLC (thinlayer chromatography), etc., can be used to generate desired levels ofthese constituents. For example, the hops resin produced bysupercritical CO₂ extraction can contain 60 wt % or more alpha acids,compared to 5 wt % to 15 wt % typically present in extracts from organicsolvents, and 1 wt % to 5 wt % present in dried hops cones. The extractcan then be fractionated so as to achieve a resin containing over 80 wt% alpha acids. Supercritical CO₂ extraction can therefore yield a resinthat is much more potent than dried hops flowers. Such a resin willcontain alpha acids, iso-alpha acids, and/or beta acids. In oneembodiment, all three types of extracted acids can be present, or inanother embodiment, alpha acids can be substantially converted toiso-alpha acids within the extract. If the desire is to convert thealpha acids to more iso-alpha acids, then the alpha acids can beisomerized by heating the high-viscosity extract with potassiumhydroxide or another mineral salt in aqueous solution. The resultinghops extract yields iso-alpha acids.

Alpha acids and beta acids can be useful in clinical applications wherereduction of inflammation, inhibition of angiogenesis, prevention ortreatment of cancer, or decreased bone loss is desired. In addition,hops acids are known to have significant anti-microbial activity. Oneexample of this is found in the brewing arts, where for centuries hopshave been added to beer, not only to add astringency and aromaticflavor, but to preserve the beer from spoilage during storage. Thiseffect is due to strong inhibition of gram-positive bacteria byiso-alpha acids and beta acids. Hops acids, particularly beta acids,have been shown to inhibit growth in a number of types bacteria thatinhabit the human body such as gastritis-causing Helicobacter pylori, aswell as oral Streptococcus bacteria such as Streptococcus mutans,Streptococcus sanguis, and Streptococcus salivarius.

Utilizing hops acids for these and other therapeutic indications can befacilitated by providing them in an aqueous form. However, the principalhigh-percentage sources for these acids—hops extract resins—are largelywater-insoluble. Therefore, in accordance with these recognitions, thepresent invention provides a method for making a water-soluble hopsextract composition. It has been discovered that non-ionic surfactantscan be used to increase or provide the solubility of hops acids incertain aqueous formulations. Therefore, a method in accordance with thepresent invention can comprise the steps of mixing a hops extract with awater-soluble non-ionic surfactant. More particularly, the process caninclude heating a volume of non-ionic surfactant while stirring ormixing it until cloudiness of the surfactant dissipates. To achievethis, the surfactant can be heated to a temperature of from 90° F. to250° F. Likewise, a hops extract resin can also be heated and mixed to atemperature of from 90° F. to 120° F. (or up to 250° F. if the goal isisomerization of the alpha acids). In this state, the desired amount ofheated hops extract can be mixed or stirred into a desired amount ofheated surfactant. The resulting composition can be a water-soluble gelthat is free of any cloudiness or visible particulates, and remains soafter it has been allowed to cool.

The amounts of extract and surfactant used will depend on the amount ofhops extract—or more particularly, of hops acids—desired to be presentin the product composition. If creating a composition having a certainhops acids content is the desired goal, then the amount of hops extractto be used will further depend on the concentrations of those acidscontained in the hops extract. The range of relative proportions ofextract and surfactant used can be limited to one extent by the minimumamount of hops acids that will be useful in the resulting composition orformulations made from it, and to the opposite extent by the minimumamount of surfactant needed to make the resulting compositionwater-soluble. According to one embodiment of the invention, an amountof hops extract can be used so as to constitute from 0.2 wt % to 70 wt %of the resulting composition, with an amount of surfactant being used soas to constitute the balance of the resulting composition, i.e. from 30wt % to 99.8 wt %.

The novel combination of hops extract and a non-ionic surfactantprovided by this invention can be an effective vehicle for administeringhops acids. Hops extracts typically contain both alpha and iso-alphaacids, so in a particular aspect, the composition of the presentinvention can also include a combination of alpha acids and iso-alphaacids. In a more particular aspect, the composition can include from0.25 wt % to 49.5 wt % of a combination of alpha and iso-alpha acids andfrom 0.05 wt % to 25 wt % beta acids. For certain applications acomposition with a higher iso-alpha acid content can be desirable. Asdescribed above, alpha acids can be converted to iso-alpha acids undercertain conditions. The conversion can be total, resulting in a productin which nearly all alpha acids have been converted to iso-alpha acidsor other derivates and little to no alpha acids remain. Therefore, inanother particular aspect of the invention, the composition can includefrom 0.25 wt % to 49.5 wt % iso-alpha acids and be substantially free ofalpha acids.

In the compositions provided by the present invention, the hops extractresin is rendered water-soluble largely through mixture with thenon-ionic surfactant. Any surfactant that has no net charge in neutralsolutions can conceivably be used in accordance with the presentinvention. Water-soluble non-ionic surfactants are preferred.Particularly, suitable non-ionic surfactants for the purposes of theinvention can be monoglycerides, diglycerides, triglycerides, mono-fattyacid esters of polyethylene glycol, di-fatty acid esters of polyethyleneglycol, sorbitan fatty acid esters, polyglycolyzed glycerides, triblockcopolymers, and mixtures thereof. Examples of non-ionic water-solublemonoglycerides, diglycerides, and triglycerides include propylene glycoldicaprylate/dicaprate, medium-chain monoglycerides and diglycerides,medium-chain triglycerides, long-chain monoglycerides, polyoxyethylenecastor oil, their derivatives, and mixtures thereof. Non-ionicwater-soluble mono-fatty acid esters and di-fatty acid esters ofpolyethyelene glycol include d-alpha-tocopheryl polyethyleneglycol 1000succinate, polyethyleneglycol 660 12-hydroxystearate, polyoxyl oleateand stearate, and their derivatives. Polyglycolyzed glycerides includepolyoxyethylated oleic glycerides, polyoxyethylated linoleic glycerides,polyoxyethylated caprylic/capric glycerides, and their derivatives. Inone embodiment of the present invention, the non-ionic surfactant is apolyoxyl castor oil. Effective polyoxyl castor oils can be synthesizedby reacting either castor oil or hydrogenated castor oil with varyingamounts of ethylene oxide. Polyoxyl 35 castor oil is available under thetrade names Cremophor EL (BASF, Inc., Ludwigshafen, Germany) and Etocas35 (Croda, Inc., Parsippany, N.J., USA), and is a mixture of 83%relatively hydrophobic and 17% relatively hydrophilic components. Themajor component of the relatively hydrophobic portion is glycerolpolyethylene glycol ricinoleate, and the major components of therelatively hydrophilic portion are polyethylene glycols and glycerolethoxylates. Polyoxyl 40 hydrogenated castor oil, is available asCremophor RH 40 (BASF, Inc.), and comprises approximately 75% relativelyhydrophobic components, of which a major portion is glycerolpolyethylene glycol 12-oxystearate.

The gel compositions provided by the present invention can be formulateddirectly into a number of products designed for a variety of uses inwhich administration of hops acids is desired. Such products can includeformulations for oral application such as toothpastes and gels, as wellas oral rinses. Such products can alternatively include formulations fortopical application, such as creams, ointments, and lotions. In additionto the surfactant, the gel compositions of the present invention caninclude additives typically used in formulating certain products. Forexample, where the composition is to be formulated into a toothpaste, itcan additionally include abrasives, bleaching agents, odorants,flavoring agents, coloring agents, sweeteners, desensitizing agents,sodium bicarbonate or other bicarbonates, anti-tartar agents,detergents, binding agents, or any combination thereof. For formulationinto topically-applied products such as creams, ointments, and lotions,the composition can additionally include emulsifiers, vitamins,minerals, preservatives, moisturizers (such as lanolin or glycerin),hormones, fragrances, coloring agents, diethanolamines, or anycombination thereof. It should be understood that these lists ofadditives are intended to be illustrative rather than exhaustive. Thosehaving skill in the relevant arts will be aware of which of these orother additives not listed here can be appropriately used for aparticular product, and any such additives can be included in accordancewith the present invention.

For certain therapeutic applications, a more dilute aqueous solution ofhops acids can be desired. Therefore, the present invention alsoprovides pharmaceutical compositions comprising an amount of the hopsextract gel composition dissolved in water, yielding a clear solution.Such a solution will therefore contain certain levels of hopsconstituents, including alpha and beta acids. The amount of theseconstituents will naturally depend on the amount of the gel compositionused as well as its chemical makeup. The color of the solution can rangefrom yellow to substantially colorless, also depending on the amount ofhops extract dissolved therein. In one embodiment, the composition caninclude from 0.0005 wt % to 24.5 wt % alpha acids and from 0.0001 wt %to 12.5 wt % beta acids. Such a composition could be useful inapplications that call for more dilute hops acids in a low-viscositypreparation. For example, quite low levels of hops acids—particularlybeta acids—can constitute an effective anti-bacterial oral treatment,serving to combat plaque buildup and gum disease. Therefore, oneexemplary use for water-based preparations such as provided by thisembodiment can be as a base ingredient for an oral rinse. Other types ofproducts incorporating this composition are also possible, as will berecognized by those having skill in the relevant art. In a moreparticular aspect, the composition can include additives such asflavoring agents, sweeteners, coloring agents, odorants, and mixturesthereof.

The compositions of the present invention are different than thosecurrently known for at least two reasons, both of which contribute toenhancing therapeutic effects when delivered to subjects. First, thesecompositions are in a liquid water-soluble form. As such, they can beincorporated into a number of products designed for administeringtherapeutically active agents. These include not only products intendedfor application on body surfaces such as skin, teeth, tongue, and gums,but also liquid products for oral administration such as elixirs. Also,the compositions of the present invention contain lower concentrationsof alpha acids than are typically found in pure hops extract. Highconcentrations of alpha acids such as are found in hops extract resinscan be associated with undesirable side effects, such as stomach gas andnausea. Administering products that contain lower concentrations ofthese acids can decrease or eliminate these side effects, resulting inhigher subject compliance in using them.

By providing hops acids in a water-soluble composition, the presentinvention also provides methods for increasing their bioavailabilitywhen ingested by a subject. The water-soluble nature of thesecompositions renders them able to enter the aqueous phase of thesubject's intestinal contents, aiding digestion and subsequentabsorption through the intestinal lining and into the bloodstream.

The compositions of the present invention have great versatility intheir application. As noted above, the widely useful properties of hopsmeans that the compositions can be used for treating various cancers,inflammatory conditions, tooth decay, gum disease, as antibiotics, asanti-fungals, as anti-viral agents, for treatment of protozoa or variousfood born pathogens, and essentially any disease or malady that hops hasbeen found to ameliorate. Therefore, the present invention providesmethods for treating such conditions in a subject, comprisingadministering water-soluble hops extract compositions to the subject.

In one embodiment, a method of treating an oral cavity of a subject cancomprise rinsing the oral cavity of a subject with an aqueous solutioncontaining hops extract. Such treatment can be to treat tooth decay,gingivitis, infection, oral diseases, or for prophylactic treatment.Such a method could involve a subject accepting a small amount of thesolution or a product made therefrom into his/her mouth, and holding itthere while using movements of the tongue to swish the solution aroundso that it is made to contact the dental and gingival surfaces. Thiscould be practiced as a part of the subject's daily hygiene regimen; forexample, the subject could rinse with the solution or product beforeand/or after brushing the teeth. Alternatively, or in addition to thepractice, the subject can use the rinse at other times of the day, suchas after meals. In another embodiment, a method of treating an oralcavity of a subject can comprise brushing the teeth and gums with atoothpaste or tooth gel that includes a hops extract gel composition.Using water-soluble hops extract compositions such as provided by thisinvention could decrease or slow tooth decay and the processes that leadto decay in a subject. It is also anticipated that its use could preventor delay the onset of tooth decay in a subject not already exhibitingthat condition.

EXAMPLES

The following Examples illustrate the embodiments of the invention thatare presently best known. However, it is to be understood that thefollowing are only exemplary or illustrative of the application of theprinciples of the present invention. Numerous modifications andalternative compositions, methods, and systems may be devised by thoseskilled in the art without departing from the spirit and scope of thepresent invention. The appended claims are intended to cover suchmodifications and arrangements. Thus, while the present invention hasbeen described above with particularity, the following Examples providefurther detail in connection with what are presently deemed to be themost practical and preferred embodiments of the invention.

Example 1

Two hundred milliliters of polyoxyl 40 Castor Oil (USP/NF) is warmedslightly while stirring until clear. Forty grams of a commerciallyavailable supercritical carbon dioxide hops extract containing 60 wt %alpha acids (24 g of alpha acids) is warmed to about 100° F. and pouredinto the castor oil with continued stirring until a golden yellow cleargel is achieved. HPLC analysis of this gel reveals it to contain 10.82wt % alpha acids and 3.2 wt % beta acids, and is pourable after cooling,exhibiting a lower viscosity than the native resin.

Example 2

The gel produced in Example 1 is added to 80 mL of warm water andbecomes completely dissolved after mixing, forming a pale yellowsolution with no undissolved particles of resin. Analysis of thissolution by HPLC reveals it to contain a level of alpha acids of 8.49 wt%.

Example 3

Fifty milliliters of polyoxyl 40 Castor oil (USP/NF) is warmed and mixeduntil clear as above. To this is added 10 grams of a warmed CO₂ extractof hops resin that has been further fractionated to contain 80 wt %alpha acids. A clear yellow water-soluble gel is formed that whenanalyzed, is found to contain 5.6 wt % alpha acids and 0.8 wt % betaacids.

Example 4

Five grams of the gel from Example 3 is mixed with 200 mL water making adilute, pale yellow mouth rinse. HPLC analysis of this solution revealsit contains 0.14 wt % alpha acids and 0.014 wt % beta acids. Thissolution is completely clear of undissolved particles of resin or othermatter.

Example 5

The dilute solution of alpha and beta acids from Example 4 is furtherdiluted in water to contain 5 μg/ml of beta acids, which would exceedthe minimum inhibitory concentration (MIC) of beta acid for inhibitinggrowth of Streptococcus mutans, the primary bacteria responsible forcausing dental caries in humans. This solution is then flavored andsweetened to produce an oral rinse to treat plaque and tooth decay.

Example 6

A mixture of polyoxyl 40 Castor Oil (USP/NF) is warmed slightly whilestirring until clear. A commercially available supercritical carbondioxide hops extract containing 60% alpha acids is warmed to about 100°F. and poured into the castor oil with continued stirring until a verypale yellow clear gel is achieved. The resultant gel has less than 1 wt% of alpha acids and less than 1 wt % beta acids.

While the invention has been described with reference to certainpreferred or illustrative embodiments, those skilled in the art willappreciate that various substitutions, modifications, changes, oromissions can be made without departing from the spirit of theinvention. It is therefore intended that the invention be limited onlyby the scope of the appended claims.

What is claimed is:
 1. A pharmaceutical gel composition, comprising:from 0.2 wt % to 70 wt % hops extract including from 0.25 wt % to 49.5wt % of a combination of alpha acids and iso-alpha acids and from 0.05wt % to 25 wt % beta acids in said composition; and from 30 wt % to 99.8wt % non-ionic surfactant selected from the group consisting ofmonoglycerides, diglycerides, triglycerides, mono-fatty acid esters ofpolyethylene glycol, di-fatty acid esters of polyethylene glycol,sorbitan fatty acid esters, polyglycolyzed glycerides, triblockcopolymers, and mixtures thereof, wherein the gel composition is free ofvisible particles of hops extract and is water-soluble.
 2. A compositionas in claim 1, wherein the non-ionic surfactant is selected from thegroup consisting of monoglycerides, diglycerides, triglycerides, andmixtures thereof.
 3. A composition as in claim 1, wherein thecomposition is formulated into a product form selected from the groupconsisting of toothpastes, creams, ointments, lotions, salves, nasalmists, and oral rinses.
 4. A composition as in claim 1, wherein thecomposition is formulated into a toothpaste.
 5. A method of treating anoral cavity of a subject, comprising applying a therapeuticallyeffective amount of the toothpaste as in claim 4 to the dental andgingival surfaces of the subject.
 6. A method as in claim 4, wherein themethod of treating is in response to tooth decay, gingivitis, infection,or oral disease.
 7. A clear pharmaceutical solution, comprising the gelcomposition of claim 1 dissolved in water or an aqueous solvent systemto yield a clear solution, wherein said solution comprises: (a) from0.0005 wt % to 24.5 wt % alpha acids; and (b) from 0.0001 wt % to 12.5wt % beta acids.
 8. A clear pharmaceutical solution as in claim 7,further comprising an additive selected from the group consisting offlavoring agents, sweeteners, coloring agents, odorants, and mixturesthereof.
 9. A method of treating an oral cavity of a subject, comprisingrinsing or contacting the oral cavity of the subject with an amount of acomposition as in claim 7 that is sufficient to treat at least one ofdental and gingival surfaces within the oral cavity.
 10. A method as inclaim 9, wherein the method of treating is in response to tooth decay,gingivitis, infection, or oral disease.
 11. A method of making awater-soluble pharmaceutical gel composition of hops extract, comprisingthe steps: heating a water-soluble non-ionic surfactant in a containerto a temperature of about 90° F. to about 250° F., while mixing thesurfactant until it is clear; heating a hops extract to a temperature ofabout 90° F. to 250° F.; and mixing an amount of the hops extract withthe surfactant so as to constitute from 0.2 wt % to 70 wt % hops extractand from 30 wt % to 99.8 wt % surfactant, wherein the hops extract issufficiently dispersed or dissolved in the surfactant so that gelcomposition contains no visible particles of hops extract.
 12. A methodas in claim 11, wherein the step of heating the water-soluble non-ionicsurfactant includes the step of stirring or mixing during the heatingstep.
 13. A method as in claim 11, wherein the step of heating the hopsextract includes the step of stirring or mixing during the heating step.14. A method as in claim 11, wherein the step of heating the hopsextract is to a temperature from 120° F. to 250° F., such thatisomerization of the hops extract occurs.
 15. A method as in claim 11,wherein the step of heating the hops extract is to a temperature from90° F. to 120° F., such that isomerization of the hops is at leastsubstantially avoided.
 16. A method of making a clear pharmaceuticalsolution, comprising dissolving or finely dispersing a gel compositionprepared in accordance with claim 11, such that the clear pharmaceuticalsolution comprises: (a) from 0.0005 wt % to 24.5 wt % alpha acids; and(b) from 0.0001 wt % to 12.5 wt % beta acids.
 17. A method as in claim16, wherein the clear pharmaceutical solution is pale in color.